This project examines the role of human homologs of genes which produce obesity in rodents, by use of linkage mapping, mutation analysis and direct measurement of the protein products of these genes. Four of the rodent obesity genes (A [agouti], ob, fat and tub) have been cloned and shown to have human homologs. The project goals are: 1) To collect and analyze for linkage to rodent and other candidate genes, nuclear and multiplex families in which obesity is segregating. Sib pair and parametric linkage analysis will be used. 2) Sequence variation will be detected by SSCP and direct sequencing of coding regions and regulatory elements. 3) Genetic screening assays will be developed for significant sequence variants to identify pre-obese individuals for study of the pathophysiologic mechanisms by which such variants lead to obesity.